The research carried out in the Natural Products Chemistry Section of LBC, NIDDK is both discovery and hypothesis driven. During FY 2006, we have been active in several related areas. These include biophysical and structural characterization of carbohydrate-binding proteins that inhibit HIV-1 entry; (ii) design of HIV?1 and HIV?2-derived gp41 peptide and protein analogs and evaluation of their properties as HIV entry inhibitors and as novel immunogens; (iii) synthesis and evaluation of mycothiol-associated enzymes in Mycobacterium tuberculosis; and (iv) discovery of new biologically active natural products.[unreadable] Several highlights of our studies in these areas are summarized next. (i) By screening the HIV- inhibitory protein MVL against a 200-member glycan library in a microarray format (Consortium for Functional Glycomics) we discovered that MVL recognizes the linear epitope [Man?(1-4)]4, or chitotetraose, in addition to the high affinity branched ligand Man3GlcNAc2. NMR experiments confirmed this result and allowed us to determine the regions of the glycan that are critical for binding to MVL. (ii) Panning of a non-immune phage library of synthetic Fabs has allowed us to identify several antibodies that inhibit HIV-1 membrane fusion at low microgram/mL concentrations by interactions with our engineered immunogen comprising a covalently linked stable trimeric coiled coil of N-peptide helices derived from gp41. In addition, we have demonstrated that our designed peptide N36-mut[e,g], that strictly targets the N-helical region of the prehairpin intermediate of gp41, acts synergistically with Nccg-gp41 (which targets the C-helical regions) when administered across constant ratios to inhibit fusion in both a cell-cell fusion assay and a neutralization assay employing pseudotyped HIV Envs. When administered together, these inhibitors yield dose reduction indices on the order of five indicative of significant synergy. (iii) We have completed the synthesis of a library of mycothiol analogs built upon a new quinic acid-derived scaffold and have identified several low micromolar inhibitors of the Mtb detoxification enzyme MCA. The synthetic scheme makes use of a polymer supported triphenyl phosphine reagent to derivatize the azide with commercially available acid chlorides. (iv) In parallel with screening cyanobacterial extracts for new carbohydrate binding proteins and HIV-1 entry inhibitors, we have been isolating new cyclic peptides from the same cyanobacterial collections. These are proving to be a rich source of new secondary metabolites exemplified by largamides A-H that were isolated from a single homogeneous collection of Oscillatoria sp. Largamides A-H comprise three different classes of cyclic peptides and depsipeptides and feature two new amino acids and two rare amino acids that have been observed once previously in peptides found in plants or fungi.